Mental Health Conditions and Hyperthyroidism.

OBJECTIVES: To evaluate the proportion of pediatric patients with concurrent diagnoses of hyperthyroidism and mental health conditions (MHCs) by using the Military Health System database. We hypothesized that the prevalence of mental health disorders would be higher in patients with hyperthyroidism compared with in the nonhyperthyroid population. METHODS: The prevalence of hyperthyroidism and MHCs was calculated by using data extracted from the Military Health System Data Repository on military beneficiaries between 10 and 18 years old who were eligible to receive care for at least 1 month during fiscal years 2008 through 2016. Prevalence ratios were used to compare MHC diagnoses in those with versus without a diagnosis of hyperthyroidism. RESULTS: There were 1894 female patients and 585 male patients diagnosed with hyperthyroidism during the study period. Prevalence ratios for MHCs in those with versus without hyperthyroidism ranged from 1.7 (attention-deficit/hyperactivity disorder [ADHD]) to 4.9 (bipolar disorder). Strikingly, suicidality was nearly 5 times more likely in patients diagnosed with hyperthyroidism than in patients who were never diagnosed with hyperthyroidism. For each of the MHCs examined, with the exception of suicidality, the MHC diagnosis was more commonly made before the diagnosis of hyperthyroidism, with the highest proportion of patients being diagnosed with ADHD before receiving a diagnosis of hyperthyroidism (68.3%). CONCLUSIONS: There is a clear association between hyperthyroidism and each of the following MHCs: ADHD, adjustment disorder, anxiety, bipolar disorder, depression, and suicidality. This study highlights the need to consider this association when evaluating patients with overlapping symptoms and for effective mental health screening tools and resources for clinicians.

A plateau in new onset type 1 diabetes: Incidence of pediatric diabetes in the United States Military Health System.

OBJECTIVES: To describe the incidence and prevalence of type 1 diabetes among pediatric dependents of the US Department of Defense. METHODS: The Military Health System (MHS) data repository was used to identify pediatric patients (≤17 years of age) with type 1 diabetes from January 1, 2007 to December 31, 2012. Annual incidence, annual prevalence and adjusted incidence were calculated and stratified by sex, age group, and region of residence. RESULTS: Within a 6-year study period from 2007 to 2012, 5616 pediatric patients with type 1 diabetes were identified; 57% male, mean (SD) age of 10.9 (4.2) years. Annual type 1 diabetes incidence (per 100 000 persons) over the 5-year time period ranged from 20.7/100 000 to 21.3/100 000. Incidence for each year was highest in the 10 to 14 years age group and ranged from 30.9/100 000 in 2008 to 35.2/100 000 in 2011. Annual type 1 diabetes prevalence (per 1000 persons) remained stable throughout the study period at 1.5/1000. Adjusted incidence for males was significantly higher compared to females (21.0/100 000 vs 18.1/100 000; P = .001). During the study period, annual incidence remained steady (test for trend, P = .984). CONCLUSIONS: The incidence of type 1 diabetes among children appears to plateau during the study period, suggesting a steady state of type 1 diabetes within this pediatric population. The MHS provides an accurate and up to date look at incidence of type 1 diabetes and may reflect broader trends of incidence of pediatric disease for the United States as a whole.

Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly.

BACKGROUND: Glycogen storage diseases (GSDs) are a collection of disorders related to glycogen synthesis or degradation that classically present in infancy with hypoglycemia, failure to thrive and hepatomegaly; however, their phenotype can vary significantly. CASE PRESENTATION: We present the cases of two children, 5 years old and 3.5 years old, who were referred to endocrinology for short stature. They were ultimately found to have hepatomegaly, fasting hypoglycemia, mild elevation of transaminases and ketosis. Laboratory and genetic studies were consistent with double heterozygosity for GSDs Ia and III, with one novel mutation discovered in each patient. Nightly, both children were treated with cornstarch, which resulted in resolution of laboratory abnormalities and improvement in their growth velocity. These cases are unusual in that GSD was diagnosed relatively late in life in patients with no previous history of severe hypoglycemia. CONCLUSIONS: They highlight the importance of considering glycogen storage disease in a child presenting with short stature, as it is a treatable disease that can be diagnosed non-invasively with genetic testing.

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Identification of Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma.

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.

Can malignant thyroid nodules be distinguished from benign thyroid nodules in children and adolescents by clinical characteristics? A review of 89 pediatric patients with thyroid nodules.

BACKGROUND: Thyroid nodules are less common in children than adults, but the risk of malignancy in thyroid nodules is much higher in children. The ability to characterize pediatric thyroid nodules has improved with the use of ultrasound-guided fine-needle aspiration, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) classification system, and expanded molecular testing. Nevertheless, stratification criteria to predict thyroid malignancy in children are poorly defined. Our objective was to determine if clinical presentation and molecular genetics could predict malignancy in pediatric thyroid nodules. METHODS: Retrospective chart review of patients ≤18 years of age at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center with the diagnosis of a thyroid nodule from January 2007 to January 2012 was conducted. Eighty-nine subjects fulfilled the inclusion criteria: 1) thyroid nodule ≥0.8 cm and biopsy (n=76), or 2) thyroid nodule ≥0.8 cm, no biopsy, and ultrasound follow-up for at least 2 years (n=13). RESULTS: Twenty-four (27%) of 89 patients were diagnosed with thyroid cancer (50% papillary thyroid carcinoma [PTC], 50% follicular variant of papillary thyroid carcinoma [FVPTC]). Features associated with malignancy included larger nodule size, palpable nodule, or palpable lymphadenopathy. There were no differences in presenting features between patients with PTC and those with FVPTC. Thyroid malignancy was diagnosed in all nine patients with a molecular abnormality (BRAF, RAS, RET/PTC, PAX8/PPARγ). CONCLUSIONS: Clinical features, FNA cytology, and molecular genetics are valuable tools to discriminate benign from malignant nodules in pediatric patients. This information is important to direct subsequent clinical management.

Neuronal T-cell autoreactivity is amplified in overweight children with new-onset insulin-requiring diabetes.

OBJECTIVE: Disease-associated T-cell autoreactivities are seen in most type 1 diabetic patients and are thought to emerge before islet autoantibodies, but host factors that impact autoimmune elements remain uncertain. We assessed if adiposity and measures of insulin sensitivity impact T- and B-cell autoimmunity in children with insulin-requiring diabetes. RESEARCH DESIGN AND METHODS: Insulin-requiring children and adolescents diagnosed between January 2004 and June 2008 were studied (n = 261): age 9.7 ± 4 years, 92% white, and 60% male. T-cell responses to 10 diabetes-associated antigens, ß-cell autoantibodies (GADA, IA-2A, IAA, and ICA), BMI z score (BMIz), and waist percentile were measured at onset and 3 months later. RESULTS: All but one subject had either T- or B-cell autoimmunity. Diabetes-associated T-cell autoreactivities were found in 92% of subjects. Higher amplitude T-cell autoreactivities to neuronal diabetes-associated autoantigens were seen in those with the highest BMIz quintile, BMI ≥85th percentile (P < 0.05), and waist circumference ≥85th percentile (P < 0.05). There were no relationships between the number of T-cell reactivities or T-cell diversity with adiposity measures or autoantibody number or type. Patients with positive T-cell reactivities but without autoantibodies had the highest BMIz (P = 0.006). CONCLUSIONS: Our observations link obesity and diabetes-related autoimmunity, suggesting an amplification of neuronal T-cell autoimmunity associated with adiposity and/or insulin resistance, with obesity-related inflammation possibly enhancing islet autoimmunity.

Preoperative cytology with molecular analysis to help guide surgery for pediatric thyroid nodules.

OBJECTIVES: To discuss the use of molecular mutation analysis in the surgical management of pediatric thyroid nodules. METHODS: This study is a case series with retrospective chart review performed at a tertiary children's hospital. Pediatric patients who presented to the Children's Hospital of Pittsburgh of UPMC with a thyroid nodule and had subsequent fine needle aspiration with positive molecular mutation between November 2009 and February 2012 were identified and charts were reviewed. Patient demographics, presenting signs, lab results, pathologic findings, and surgical outcomes were collected. RESULTS: 5 pediatric patients with positive molecular mutation studies on preoperative FNA were identified. FNA results were categorized as follows: suspicious for follicular neoplasm (n = 2), suspicious for malignant cells (n = 1), and positive for malignant cells (n = 2). The following molecular mutations were identified: BRAF (V600E) (n = 2), PAX8/PPARγ (n = 1), HRAS (n = 1), and RET/PTC (n = 1). A total thyroidectomy was performed on each patient. In all cases the final pathology was positive for malignancy (papillary thyroid carcinoma (PTC), n = 3; follicular variant of PTC, n = 2). Three of five patients had transient postsurgical hypocalcemia. There were no other postoperative complications. CONCLUSIONS: This series provides evidence that preoperative FNA with reflex molecular testing in pediatric thyroid nodules can help guide surgical decision making, reduce the need for repeat surgeries, and diminish the risk of complications from a staged procedure.

Efficacy of neonatal release of ankyloglossia: a randomized trial.

BACKGROUND: Ankyloglossia has been associated with a variety of infant-feeding problems. Frenotomy commonly is performed for relief of ankyloglossia, but there has been a lack of convincing data to support this practice. OBJECTIVES: Our primary objective was to determine whether frenotomy for infants with ankyloglossia improved maternal nipple pain and ability to breastfeed. A secondary objective was to determine whether frenotomy improved the length of breastfeeding. METHODS: Over a 12-month period, neonates who had difficulty breastfeeding and significant ankyloglossia were enrolled in this randomized, single-blinded, controlled trial and assigned to either a frenotomy (30 infants) or a sham procedure (28 infants). Breastfeeding was assessed by a preintervention and postintervention nipple-pain scale and the Infant Breastfeeding Assessment Tool. The same tools were used at the 2-week follow-up and regularly scheduled follow-ups over a 1-year period. The infants in the sham group were given a frenotomy before or at the 2-week follow-up if it was desired. RESULTS: Both groups demonstrated statistically significantly decreased pain scores after the intervention. The frenotomy group improved significantly more than the sham group (P < .001). Breastfeeding scores significantly improved in the frenotomy group (P = .029) without a significant change in the control group. All but 1 parent in the sham group elected to have the procedure performed when their infant reached 2 weeks of age, which prevented additional comparisons between the 2 groups. CONCLUSIONS: We demonstrated immediate improvement in nipple-pain and breastfeeding scores, despite a placebo effect on nipple pain. This should provide convincing evidence for those seeking a frenotomy for infants with signficant ankyloglossia.